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- PDB-4a92: Full-length HCV NS3-4A protease-helicase in complex with a macroc... -

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Basic information

Entry
Database: PDB / ID: 4a92
TitleFull-length HCV NS3-4A protease-helicase in complex with a macrocyclic protease inhibitor.
ComponentsSERINE PROTEASE NS3
KeywordsHYDROLASE / DRUG DESIGN
Function / homology
Function and homology information


hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / SH3 domain binding / nucleoside-triphosphate phosphatase ...hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / SH3 domain binding / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / ribonucleoprotein complex / induction by virus of host autophagy / RNA-directed RNA polymerase / virus-mediated perturbation of host defense response / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
RNA Helicase; Chain A, domain 3 / RNA Helicase Chain A , domain 3 / Thrombin, subunit H - #120 / : / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 ...RNA Helicase; Chain A, domain 3 / RNA Helicase Chain A , domain 3 / Thrombin, subunit H - #120 / : / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal / Hepatitis C virus non-structural protein NS4b / Hepatitis C virus capsid protein / Hepatitis C virus, Non-structural protein NS2 / Hepatitis C virus, Non-structural 5a protein / Hepatitis C virus, Non-structural 5a protein, domain 1a / Hepatitis C virus non-structural 5a, 1B domain / NS5A domain 1a superfamily / Hepatitis C virus non-structural 5a protein membrane anchor / Hepatitis C virus non-structural 5a zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus, Non-structural protein NS4a / Hepatitis C virus non-structural protein NS4a / Hepatitis C virus, Core protein, C-terminal / Hepatitis C virus core protein / Hepatitis C virus, Non-structural protein E2/NS1 / Hepatitis C virus non-structural protein E2/NS1 / Hepatitis C virus, Envelope glycoprotein E1 / Hepatitis C virus envelope glycoprotein E1 / RNA dependent RNA polymerase, hepatitis C virus / Viral RNA dependent RNA polymerase / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / DEAD box, Flavivirus / Flavivirus DEAD domain / Trypsin-like serine proteases / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Thrombin, subunit H / P-loop containing nucleotide triphosphate hydrolases / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-F9K / Genome polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.73 Å
AuthorsSchiering, N. / D'Arcy, A. / Simic, O. / Eder, J. / Raman, P. / Svergun, D.I. / Bodendorf, U.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2011
Title: A Macrocyclic Hcv Ns3/4A Protease Inhibitor Interacts with Protease and Helicase Residues in the Complex with its Full- Length Target.
Authors: Schiering, N. / D'Arcy, A. / Villard, F. / Simic, O. / Kamke, M. / Monnet, G. / Hassiepen, U. / Svergun, D.I. / Pulfer, R. / Eder, J. / Raman, P. / Bodendorf, U.
History
DepositionNov 23, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2011Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2012Group: Other
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AC" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AC" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "BC" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: SERINE PROTEASE NS3
B: SERINE PROTEASE NS3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,5146
Polymers141,6472
Non-polymers1,8674
Water3,639202
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3140 Å2
ΔGint-87.5 kcal/mol
Surface area51640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.972, 110.470, 137.227
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-0.9003, -0.4353, 0.005456), (-0.4352, 0.9002, 0.01524), (-0.01154, 0.01134, -0.9999)
Vector: 69.87, 14.54, 212.7)

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Components

#1: Protein SERINE PROTEASE NS3 / NS3-4A / HEPACIVIRIN / NS3P / P70


Mass: 70823.406 Da / Num. of mol.: 2 / Fragment: PROTEASE/HELICASE / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: MACROCYCLIC ACYLSULFONAMIDE PROTEASE INHIBITOR / Source: (gene. exp.) HEPATITIS C VIRUS / Strain: 1B / Variant: BK / Plasmid: PET28A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P26663, hepacivirin, nucleoside-triphosphate phosphatase, RNA helicase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-F9K / (1'R,2R,2'S,6S,24AS)-17-FLUORO-6-(1-METHYL-2-OXOPIPERIDINE-3-CARBOXAMIDO)-19,19-DIOXIDO-5,21,24-TRIOXO-2'-VINYL-1,2,3,5,6,7,8,9,10,11,12,13,14,20,21,23,24,24A-OCTADECAHYDROSPIRO[BENZO[S]PYRROLO[2,1-G][1,2,5,8,18]THIATETRAAZACYCLOICOSINE-22,1'-CYCLOPRO-2-CARBOXYLATEPAN]-2-YL 4-FLUOROISOINDOLINE


Mass: 867.958 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C42H51F2N7O9S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 202 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsDOUBLE-MUTANT E628A, T631L

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.46 Å3/Da / Density % sol: 50 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.5
Details: PROTEIN AT 8.75 MG/ML IN 25MM TRIS PH 7.5, 10% GLYCEROL, 1M NACL, 1MM TCEP, 0.1% BETA-OCTYL-GLUCOSIDE; HANGING DROP VAPOR DIFFUSION. RESERVOIR: 20% PME2000, 200 MM NA THIOCYANATE; MICRO-SEEDED (SEED-BEAD).

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99988
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 10, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99988 Å / Relative weight: 1
ReflectionResolution: 2.73→76.4 Å / Num. obs: 37797 / % possible obs: 99.8 % / Observed criterion σ(I): 1 / Redundancy: 4.5 % / Biso Wilson estimate: 57.35 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 17.2
Reflection shellResolution: 2.73→2.81 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 4.6 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.9.6refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2.73→76.4 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.9001 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.317
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=ZN. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=9846. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=0. ...Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=ZN. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=9846. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=0. NUMBER TREATED BY BAD NON-BONDED CONTACTS=2. DISORDERED REGIONS, E.G. B183-B185, WERE MODELED STEREOCHEMICALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2305 1890 5 %RANDOM
Rwork0.178 ---
obs0.1807 37797 99.84 %-
Displacement parametersBiso mean: 55.14 Å2
Baniso -1Baniso -2Baniso -3
1--6.9106 Å20 Å20 Å2
2--4.05 Å20 Å2
3---2.8606 Å2
Refine analyzeLuzzati coordinate error obs: 0.312 Å
Refinement stepCycle: LAST / Resolution: 2.73→76.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9522 0 124 202 9848
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019874HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1913498HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3196SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes168HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1484HARMONIC5
X-RAY DIFFRACTIONt_it9874HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.27
X-RAY DIFFRACTIONt_other_torsion18.74
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1352SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact11262SEMIHARMONIC4
LS refinement shellResolution: 2.73→2.81 Å / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.2694 145 4.99 %
Rwork0.2075 2759 -
all0.2109 2904 -
obs--99.84 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.11910.0509-0.11850.29280.33010.60570.0184-0.0626-0.0062-0.0940.0546-0.0839-0.07410.022-0.0730.0219-0.02080.0655-0.0532-0.0278-0.015240.631771.149798.4052
20.70050.1244-0.3540.1863-0.10070.4797-0.01840.0451-0.0496-0.0460.0480.00520.0486-0.139-0.0297-0.0223-0.018-0.0172-0.04070.0035-0.03333.001762.3828114.964
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A
2X-RAY DIFFRACTION2CHAIN B

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